1. Technical Field
This invention relates in general to a process for removing ruthenium or ruthenium-containing compounds from reaction mixtures using supercritical fluid processing techniques. This invention has particular application for removing ruthenium-containing catalyst and ruthenium-containing by products from reaction mixtures resulting from ring-closing olefin metathesis (RCM) reactions.
2. Background Information
The olefin metathesis reaction has become an important method in organic synthesis (see for example R. H. Grubbs and S. Chang, Tetrahedron 1998, 54, 4413; D. L. Wright, Curr. Org. Chem., 1999, 3, 211; A. Fürstner, Angew. Chem. Int. Ed. Engl., 2000, 39, 3012). In this reaction, two alkenes are joined to form a new olefin having one carbon from each original alkene. The reaction takes place in the presence of a metal carbene catalyst.
In general there are three types of olefin metathesis reactions: ring-opening metathesis polymerization, acyclic cross metathesis and ring-closing metathesis (RCM). The RCM is an effective means to prepare cyclic compounds from a diolefin (FIG. 1).
The reaction can be used to prepare various sized rings and it tolerates heteroatoms and various functional groups in the molecule. Popular catalytic reactive species for olefin metathesis reactions include ruthenium and molybdenum carbenes generated from precatalyst complexes such as the ruthenium vinylidene complex shown in FIG. 2 (Grubb's catalyst, G. Fu and R. H. Grubbs, J. Am. Chem. Soc. 1992, 114, 5426).

While providing a valuable tool for the synthesis of complex organic molecules, the olefin metathesis reaction does have some complications. Use of the catalyst may result in formation of potentially undesirable, highly colored by-products that are difficult to remove. The presence of these by-products is not acceptable in pharmaceuticals. Often several chromatographic steps are required to remove such by-products. Furthermore, if the impurities are not removed they can cause further problems including decomposition and double-bond migration.
A number of techniques have been reported to remove ruthenium by-products from olefin metathesis reaction mixtures. One technique uses a water-soluble phosphine ligand to coordinate with the ruthenium and facilitate removal by aqueous extraction (H. D. Maynard and R. H. Grubbs, Tetrahedron Letters 1999, 40, 4137). Another method reported in the literature involves stirring for several hours with lead tetraacetate to oxidize the ruthenium by-products followed by filtration through silica gel (L. A. Paquette et al., Org. Lett. 2000, 2, 1259). A third method involves treatment of the crude reaction mixture with triphenylphosphine oxide or DMSO followed by a chromatographic filtration through silica gel (Y. M. Ahn et al., Org. Lett. 2001, 3, 1411). Treatment of the reaction mixture with silica gel and activated carbon followed by chromatography on silica gel is described in another method (J. H. Cho and B. M. Kim, Org. Lett., 2003, 5, 531).
However, each of the above techniques still suffer from disadvantages that make them undesirable for large-scale preparations or for pharmaceuticals. They introduce new, potentially toxic entities which also may not be chemically compatible with the desired reaction product that is being purified. The water soluble ligand is expensive and needs to be used in large excess relative to the by-products being removed. Each method requires either extractions or chromatographic filtrations that are both tedious and add to the processing time. Furthermore, these methods chemically modify the ruthenium catalyst which complicates or eliminates the possibility of catalyst recycling.
The macrocyclic compounds of the following formula (I) and methods for their preparation are known from: Tsantrizos et al., U.S. Pat. No. 6,608,027 B1; Llinas Brunet et al, U.S. Application Publication No. 2003/0224977 A1; Llinas Brunet et al, U.S. application Ser. No. 10/686,755, filed Oct. 16, 2003; Llinas Brunet et al, U.S. application Ser. No. 10/945,518, filed Sep. 20, 2004; Brandenburg et al., U.S. application Ser. No. 10/818,657, filed Apr. 6, 2004 and WO 2004/092203; Samstag et al., U.S. application Ser. No. 10/813,344, filed Mar. 30, 2004, and WO 2004/089974, all of which are herein incorporated by reference:
wherein    RA is a leaving group or a group of formula II
    W is CH or N,    L0 is H, halo, C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, C1-6 alkoxy, C3-6 cycloalkoxy, hydroxy, or N(R23)2,    wherein each R23 is independently H, C1-6 alkyl or C3-6 cycloalkyl;    L1, L2 are each independently H, halogen, C1-4alkyl, —O—C1-4alkyl, or —S—C1-4alkyl (the sulfur being in any oxidized state); or    L0 and L1 or    L0 and L2 may be covalently bonded to form together with the two C-atoms to which they are linked a 4-, 5- or 6-membered carbocyclic ring wherein one or two (in the case of a 5- or 6-membered ring) —CH2— groups not being directly bonded to each other, may be replaced each independently by —O— or NRa wherein Ra is H or C1-4alkyl, and wherein said ring is optionally mono- or di-substituted with C1-4 alkyl;    R22 is H, halo, C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, C1-6 thioalkyl, C1-6 alkoxy, C3-6 cycloalkoxy, C2-7 alkoxyalkyl, C3-6 cycloalkyl, C6 or C10 aryl or Het, wherein Het is a five-, six-, or seven-membered saturated or unsaturated heterocycle containing from one to four heteroatoms selected from nitrogen, oxygen and sulfur;    said cycloalkyl, aryl or Het being substituted with R24,    wherein R24 is H, halo, C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, C3-6 cycloalkoxy, NO2, N(R25)2, NH—C(O)—R25; or NH—C(O)—NH—R25, wherein each R25 is independently: H, C1-6 alkyl or C3-6 cycloalkyl;    or R24 is NH—C(O)—OR26 wherein R26 is C1-6 alkyl or C3-6 cycloalkyl;    R3 is hydroxy, NH2, or a group of formula —NH—R9, wherein R9 is C6 or 10 aryl, heteroaryl, —C(O)—R20, —C(O)—NHR20 or —C(O)—OR20, wherein R20 is C1-6 alkyl or C3-6 cycloalkyl;    D is a 5 to 10 atom saturated or unsaturated alkylene chain optionally containing one to three heteroatoms independently selected from: O, S or N—R27, wherein R27 is H, C1-6alkyl, C3-6cycloalkyl or C(O)R28, wherein R28 is C1-6alkyl, C3-6cycloalkyl or C6 or 10 aryl;    R4 is H, or from one to three substituents at any carbon atom of said chain D, said substituent independently selected from the group consisting of: C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, hydroxy, halo, amino, oxo, thio, or C1-6 thioalkyl; and    A is an amide of formula —C(O)—NH—R11, wherein R11 is selected from the group consisting of: C1-8 alkyl, C3-6 cycloalkyl, C6 or 10 aryl, C7-16 aralkyl, or SO2R5A wherein R5A is C1-8 alkyl, C3-7 cycloalkyl, C1-6 alkyl-C3-7 cycloalkyl;    or A is a carboxylic acid or a pharmaceutically acceptable salt or ester thereof.
The compounds of formula (I) are disclosed in the above-mentioned patent documents as being active agents for the treatment of hepatitis C virus (HCV) infections, or as intermediates useful for the preparation of such anti-HCV agents as described therein, and are prepared therein via RCM of an acyclic diolefin using ruthenium-based catalysts. In these previous processes, the cyclized product is purified by either column chromatography or using a scavenging agent, such as trishydroxymethylphosphine (THP), to effect removal of the ruthenium by-product from the reaction mixture. However, such processes suffer from the same disadvantages as described above, making them undesirable for large-scale preparations or for pharmaceuticals.
We describe herein a method for removing the ruthenium catalyst by-products from the cyclized product of formula (I) that does not suffer from the disadvantages described above. The process of the present invention employs supercritical fluid processing as a technique to separate the macrocyclic product of formula (I) from the ruthenium catalyst by-products.
It has been reported that supercritical carbon dioxide may be used as a versatile reaction medium for conducting certain olefin metathesis reactions, and in the case of ring-closing olefin metathesis (RCM) reactions, the solubility properties of the supercritical carbon dioxide may be exploited to isolate the low molecular weight RCM products from the ruthenium complex via selective supercritical fluid extraction (Furstner et al., J. Am. Chem. Soc., 2001, 123, 9000; W. Leitner, C. R. Acad. Sci. Paris, Serie IIc, Chimie, 2000, 3, 595; Furstner et al., Angew. Chem., 1997, 109, 2562, and Angew. Chem. Int. Ed. Engl., 1997, 36, 2466). However, although numerous examples are provided using lower molecular weight RCM products, there is no disclosure or suggestion that such technique would be effective to extract and separate higher molecular weight RCM products, such as the compounds of formula (I), from the ruthenium by-products.